title: The impact of the receptor binding profiles of the vascular endothelial growth factors on their angiogenic features.
abstract: BACKGROUND
  Vascular endothelial growth factors (VEGFs) are potential therapeutic agents for treatment of ischemic diseases. Their angiogenic effects are mainly mediated through VEGF receptor 2 (VEGFR2).
  
  
  METHODS
  Receptor binding, signaling, and biological efficacy of several VEGFR2 ligands were compared to determine their characteristics regarding angiogenic activity and vascular permeability.
  
  
  RESULTS
  Tested VEGFR2 ligands induced receptor tyrosine phosphorylation with different efficacy depending on their binding affinities. However, the tyrosine phosphorylation pattern and the activation of the major downstream signaling pathways were comparable. The maximal angiogenic effect stimulated by different VEGFR2 ligands was dependent on their ability to bind to co-receptor Neuropilin (Nrp), which was shown to form complexes with VEGFR2. The ability of these VEGFR2 ligands to induce vascular permeability was dependent on their concentration and VEGFR2 affinity, but not on Nrp binding.
  
  
  CONCLUSIONS
  VEGFR2 activation alone is sufficient for inducing endothelial cell proliferation, formation of tube-like structures and vascular permeability. The level of VEGFR2 activation is dependent on the binding properties of the ligand used. However, closely similar activation pattern of the receptor kinase domain is seen with all VEGFR2 ligands. Nrp binding strengthens the angiogenic potency without increasing vascular permeability.
  
  
  CONCLUSIONS
  This study sheds light on how different structurally closely related VEGFR2 ligands bind to and signal via VEGFR2/Nrp complex to induce angiogenesis and vascular permeability. The knowledge of this study could be used for designing VEGFR2/Nrp ligands with improved therapeutic properties.
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, FI-70211 Kuopio, Finland. Electronic address: tiina.nieminen@uef.fi.
authors.forename: Tiina
authors.initials: T
authors.lastname: Nieminen
authors.forename: Pyry I
authors.initials: PI
authors.lastname: Toivanen
authors.forename: Nina
authors.initials: N
authors.lastname: Rintanen
authors.forename: Tommi
authors.initials: T
authors.lastname: Heikura
authors.forename: Suvi
authors.initials: S
authors.lastname: Jauhiainen
authors.forename: Kari J
authors.initials: KJ
authors.lastname: Airenne
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Varpu
authors.initials: V
authors.lastname: Marjomäki
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D002199:Capillary Permeability; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D010957:Plasmids; D015398:Signal Transduction; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenesis; HEK293T cells; HSPGs; HUVECs; Heat shock protein 27; His-tag; Hsp27; Neuropilin; Nrp; PAE cells; PLCγ; PlGF; Receptor activation; T-cell-specific adapter; TSAd; VE-cadherin; VEGF; VEGF receptor 2; VEGFR2; Vascular endothelial growth factor; heparan sulfate proteoglycans; hexahistidine tag; human embryonic kidney 293T cells; human umbilical vein endothelial cells; phospholipase Cγ; placenta growth factor; porcine aortic endothelial cells; sNrp1-Fc; soluble Nrp1 IgG Fc fragment fusion protein; vascular endothelial cadherin; vascular endothelial growth factor